National Cancer Institute

at the National Institutes of Health

Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)

Health Professional Version

Table of Contents

General Information About Childhood Non-Hodgkin Lymphoma (NHL)

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with
cancer should be referred to medical centers that have a multidisciplinary team
of cancer specialists with experience treating the cancers that occur during
childhood and adolescence. This multidisciplinary team approach incorporates the skills
of the primary care physician, pediatric surgical subspecialists, radiation
oncologists, pediatric medical oncologists/hematologists, rehabilitation
specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation
that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for
pediatric cancer centers and their role in the treatment of children with
cancer have been outlined by the American Academy of Pediatrics.[2] At these
pediatric cancer centers, clinical trials are available for most of the
types of cancer that occur in children and adolescents, and the opportunity to
participate in these trials is offered to most patients/families. Clinical
trials for children and adolescents with cancer are generally designed to
compare potentially better therapy with therapy that is currently accepted as
standard. Most of the progress made in identifying curative therapies
for childhood cancers has been achieved through clinical trials. Information
about ongoing clinical trials is available from the NCI
Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For non-Hodgkin lymphoma (NHL), the 5-year survival rate has increased over the same time period from 45% to 88% in children younger than 15 years and from 47% to 77% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Epidemiology

Lymphoma (Hodgkin lymphoma and NHL) is the third most common childhood
malignancy, and NHL accounts for approximately 7% of
cancers in children younger than 20 years.[3,4] In the United States,
about 800 new cases of NHL are diagnosed each year. The incidence is
approximately ten cases per million people per year. The incidence of NHL observed in children and adolescents varies depending on age, histology, gender, and race.[3] Although there is no sharp age peak, childhood NHL
occurs most commonly in the second decade of life, and occurs infrequently
in children younger than 3 years.[3] NHL in infants is very rare (1% in Berlin-Frankfurt-Munster [BFM] trials from 1986 to 2002).[5] The incidence of NHL is increasing overall, which is accounted for because of a slight increase in the incidence for those aged 15 to 19 years; however, the incidence of NHL in children younger than 15 years has remained constant over the past several decades.[3]

Childhood NHL is more common in males than in females, with the exception of primary mediastinal B-cell lymphoma, in which the incidence is almost the same in males and females.[3,6] A review of Surveillance, Epidemiology, and End Results (SEER) data on Burkitt lymphoma diagnosed in the United States between 1992 and 2008 revealed 2.5 cases/million person-years with more cases in males than in females (3.9:1.1). The incidence of diffuse large B-cell lymphoma increases with age in both males and females. The incidence of lymphoblastic lymphoma remains relatively constant across ages for both males and females.

The incidence and age distribution of specific types of NHL according to gender is described in Table 1.

bIn older adolescents, indolent and aggressive histologies (more commonly seen in adult patients) are beginning to be found.

Males

Females

Age (y)

<5

5–9

10–14

15–19

<5

5–9

10–14

15–19

Burkitt

3.2

6

6.1

2.8

0.8

1.1

0.8

1.2

Lymphoblastic

1.6

2.2

2.8

2.2

0.9

1.0

0.7

0.9

DLBCL

0.5

1.2

2.5

6.1

0.6

0.7

1.4

4.9

Other (mostly ALCL)

2.3

3.3

4.3

7.8b

1.5

1.6

2.8

3.4b

The incidence of NHL is higher in whites than in African Americans, and Burkitt lymphoma is more frequent in non-Hispanic whites (3.2 cases/million person-years) than in Hispanic whites (2.0 cases/million person-years).[7]

Relatively little is known of the epidemiology of childhood NHL. However, immunodeficiency, both congenital and acquired (human immunodeficiency virus infection [HIV] or posttransplant immunodeficiency), increases the risk of NHL. Epstein-Barr virus (EBV) is associated with most cases of NHL seen in the immunodeficient population.[3]
Although 85% or more of Burkitt lymphoma is associated with the EBV in endemic Africa, approximately 15% of cases in Europe or the United States will have EBV detectable in the tumor tissue.[8]

NHL presenting as a secondary malignancy is rare in pediatrics. A retrospective review of the German Childhood Cancer Registry identified 11 (0.3%) of 2,968 newly diagnosed children older than 20 years with NHL as having a secondary malignancy.[9] In this small cohort, outcome was similar to patients with de novo NHL when treated with standard therapy.[9]

Prognostic Factors for Childhood NHL

With current treatments, more than 80% of children and adolescents with NHL will survive at least 5
years, though outcome is variable depending on a
number of factors, including clinical stage and histology.[10]

Prognostic factors for childhood NHL include the following:

Age: NHL in infants is rare (1% in Berlin-Frankfurt-Munster [BFM] trials from 1986 to 2002).[5] In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.[5]

Adolescents have been reported to have inferior outcome compared with younger children.[10-13] A review of survival for various subtypes of NHL in children and adolescents between 1986 and 2007 has been reported by the BFM group.[13] Event-free survival (EFS) was 79% for adolescents and 85% for children. This adverse affect of age appears to be most pronounced for adolescents with T-cell lymphoblastic lymphoma and diffuse large B-cell lymphoma compared with children with these diagnoses.[13] The poorer outcome of patients older than 15 years appears to be attributable primarily to patients with diffuse large B-cell lymphoma.[10] On the other hand, for patients with Burkitt and Burkitt-like lymphoma on the FAB LMB 96 (COG-C5961) clinical trial, adolescent age (≥ 15 years) was not an independent risk factor for inferior outcome, with 3-year EFS of 89% ± 1.0% for children younger than 15 years and 84% ± 3.4% for patients aged 15 years and older.[14]

Site of disease: In general, patients with low-stage disease (i.e., single extra-abdominal/extrathoracic tumor or totally resected intra-abdominal tumor) have an excellent prognosis (a 5-year survival rate of approximately 90%), regardless of histology.[15-20] Patients with NHL arising in bone have an excellent prognosis, regardless of histology.[21,22] Testicular involvement does not affect prognosis.[16,17,23] As opposed to adults, mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[10,14,15,18] For patients with primary mediastinal B-cell lymphoma, 3-year EFS is 50% to 70%,[14,15,18,24] and for patients with central nervous system (CNS) disease at presentation, the 3-year EFS is 70%.[14,18,25]

In anaplastic large cell lymphoma, a retrospective study by the European Intergroup for Childhood NHL (EICNHL) found a high-risk group of patients defined by involvement of mediastinum, skin, or viscera.[26] An immune response against the ALK protein (i.e., anti-ALK antibody titer) appears to correlate with lower clinical stage and absence of these clinical risk features (mediastinal and visceral organ involvement) and predicts relapse risk but not overall survival.[27] However, in the CCG-5941 study for anaplastic large cell lymphoma patients, only bone marrow involvement predicted inferior progression-free survival.[28][Level of evidence: 2A] Patients with leukemic involvement (>25% blasts in marrow) or CNS involvement at diagnosis require intensive therapy.[17,25,29] Although these intensive therapies have improved the outcome for patients with high-stage (stage III or IV) or advanced-stage disease, patients who present with CNS disease have the worst outcome.[17,25,29,30] The combination of CNS involvement and marrow disease appears to impact outcome the most for Burkitt lymphoma/leukemia.[25] Patients with leukemic
disease only, and no CNS disease, had a 3-year EFS of 90%, while patients with CNS disease at presentation had a 70% 3-year EFS.[25]

Chromosomal abnormalities: Though data for cytogenetics is less robust than for childhood leukemia, some chromosomal abnormalities have been reported to have prognostic value.

For pediatric Burkitt lymphoma patients, secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome,[31,32] and cytogenetic abnormalities involving gain of 7q or deletion of 13q appear to have an inferior outcome on current chemotherapy protocols.[32,33]

For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcome appears to be lower.[32]

The BFM group reported that in pediatric patients with T-cell lymphoblastic lymphoma, loss of heterozygosity at chromosome 6q was observed in 12% (25 of 217) of patients and was associated with unfavorable prognosis (probability of EFS [pEFS], 27% vs. 86%, P <.0001).[34,35] NOTCH1 mutations were seen in 60% (70 of 116) of patients and were associated with favorable prognosis (pEFS, 84% vs. 66%; P = .021). NOTCH1 mutations were rarely seen in patients with loss of heterozygosity in 6q16.[34]

Tumor burden: A surrogate for tumor burden (i.e., elevated levels of lactate dehydrogenase) has been shown to be prognostic in many studies.[14,15,18,24]

More recently, detection of minimal disease at diagnosis or minimal residual disease (MRD) appears to be prognostic in most subtypes of childhood NHL. In a retrospective subset analysis, there was evidence that submicroscopic bone marrow and peripheral blood involvement, detected by reverse transcription-polymerase chain reaction (RT-PCR) from NPM-ALK, was found in approximately 50% of patients and correlated with clinical stage;[36] marrow involvement detected by PCR was associated with a 50% cumulative incidence of relapse. The prognostic role of MRD in the treatment of Burkitt leukemia remains unclear.[37-39]

Response to therapy: One of the most important predictive factors for Burkitt lymphoma/leukemia is response to the initial prophase treatment; poor responders (i.e., <20% resolution of disease) had an EFS of 30%.[15] Results from two studies suggest inferior outcome for patients with Burkitt leukemia that had detectable MRD after induction chemotherapy.[37,38]

References

Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997. [PUBMED Abstract]

Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005. [PUBMED Abstract]

Cellular Classification of Childhood NHL

Cellular Classification and Clinical Presentation

In children, non-Hodgkin lymphoma (NHL) is distinct from the more common
forms of lymphoma observed in adults. While lymphomas in adults are more commonly
low or intermediate grade, almost all NHL that occurs in children is high grade.[1-3] The World Health Organization (WHO) has classified NHL on the basis of the following: (1) phenotype (i.e., B-lineage and T-lineage or natural killer [NK] cell lineage) and (2) differentiation (i.e., precursor vs. mature).[4]

On the basis of clinical response to treatment, NHL of childhood and adolescence currently falls into the following three therapeutically relevant categories:

NHL associated with immunodeficiency generally has a mature B-cell phenotype and is more often of large cell than Burkitt histology.[5] Posttransplant lymphoproliferative diseases are classified according to WHO nomenclature as (1) early lesions, (2) polymorphic, and (3) monomorphic.[6] While the majority of posttransplant lymphoproliferative diseases are of B-cell phenotype, approximately 10% are mature (peripheral) T-cell lymphomas.[6]

Other types of lymphoma, such as peripheral T-cell lymphoma, T/NK lymphomas, cutaneous lymphomas, and indolent B-cell lymphomas (e.g., follicular lymphoma), are more commonly seen in adults and occur rarely in children. Refer to the following PDQ summaries for more information:

Each type of childhood NHL is associated with distinctive molecular biological
characteristics, which are outlined in the following table. The Revised
European-American Lymphoma (REAL) classification and the WHO classification are the most current NHL classifications
utilized and are shown below.[2] The Working Formulation is also listed for
reference. The WHO classification applies the principles of the REAL
classification and focuses on the specific type of lymphoma for therapy
purposes. For the most part, the remaining categories do not pertain
to pediatric NHL and are not shown.

Table 2. Major Histopathological Categories of Non-Hodgkin Lymphoma in
Children and Adolescentsa

Burkitt and Burkitt-like lymphoma/leukemia

Burkitt and Burkitt-like lymphoma/leukemia in the United States accounts for about 30% of childhood NHL and exhibits consistent, aggressive clinical behavior.[2,3,7] The overall incidence of Burkitt lymphoma is 2.5 cases per million person-years and is higher among boys than girls (3.9 vs. 1.1).[2,8] The most common primary sites of disease are the abdomen and the lymph nodes, especially of the head and neck region.[3,8] Other sites of involvement include testes, bone, skin, bone marrow, and central nervous system (CNS).

The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase (TdT). These malignant cells usually express surface immunoglobulin, most bearing surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD20, CD22) are usually present, and almost all childhood Burkitt/Burkitt-like lymphoma/leukemia express CALLA (CD10). Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the c-myc oncogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, a gene involved in cellular proliferation.[3]

The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma consists of uniform, small, noncleaved cells, whereas Burkitt-like lymphoma is a highly disputed diagnosis among pathologists because of features that are consistent with diffuse large B-cell lymphoma.[9] Cytogenetic evidence of c-myc rearrangement is the gold standard for diagnosis of Burkitt lymphoma. For cases in which cytogenetic analysis is not available, the WHO has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma or with more pleomorphism, large cells, and a proliferation fraction (i.e., Ki-67[+] of ≥99%).[7] Studies have demonstrated that the vast majority of Burkitt-like or “atypical Burkitt” lymphomas have a gene expression signature similar to Burkitt lymphoma.[10] Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma.[10,11] Despite the histologic differences, Burkitt and Burkitt-like lymphoma/leukemia are clinically very aggressive and are treated with very aggressive regimens.[12-15]

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma is a mature B-cell neoplasm that represents 10% to 20% of pediatric NHL.[2,3,16] Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade.[2,17,18] The WHO classification system does not recommend morphologic subclassification based on morphologic variants (e.g., immunoblastic, centroblastic) of diffuse large B-cell lymphoma.[19] Pediatric diffuse large B-cell lymphoma may present clinically similar to Burkitt or Burkitt-like lymphoma, though it is more often localized and less often involves the bone marrow or CNS.[16,17,20]

About 20% of pediatric diffuse large B-cell lymphoma presents as primary mediastinal disease (primary mediastinal B-cell lymphoma). This presentation is more common in older children and adolescents and has been associated with an inferior outcome compared with other pediatric diffuse large B-cell lymphoma.[13,14,17,21-23] In a study of adolescents with stage III primary mediastinal large B-cell lymphoma treated with FAB/LMB-96 (NCT00002757) therapy, the 5-year event-free survival (EFS) was 66%, versus 85% for adolescents with nonmediastinal diffuse large B-cell lymphoma.[24][Level of evidence: 2A] However, a single-arm study in adults showed excellent disease-free survival utilizing the DA-EPOCH-R regimen (dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab; usually six cycles) with filgrastim and no radiation therapy. The 5-year EFS was 93% and overall survival (OS) was 97%.[25][Level of evidence: 2A] At 10 years poststudy, there was no evidence of cardiac toxicity. This is currently being tested in pediatric clinical trials.

Primary mediastinal B-cell lymphoma is associated with distinctive chromosomal aberrations (gains in chromosome 9p and 2p in regions that involve JAK2 and c-rel, respectively) [22,23] and commonly shows inactivation of SOCS1 by either mutation or gene deletion.[26,27] Primary mediastinal B-cell lymphoma also has a distinctive gene expression profile in comparison with other diffuse large B-cell lymphoma, suggesting a close relationship of primary mediastinal B-cell lymphoma with Hodgkin lymphoma.[28,29]

With the exception of primary mediastinal B-cell lymphoma, diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults. The vast majority of pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[18,30,31] Unlike adult diffuse large B-cell lymphoma of the germinal center B-cell type, in which the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene is commonly observed, pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation.[18] As many as 30% of patients younger than 14 years with diffuse large B-cell lymphoma will have a gene signature similar to Burkitt lymphoma.[10] A subset of pediatric diffuse large B-cell lymphoma cases were found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than adults (15% vs. 2%), were germinal center–derived B-cell lymphomas, and were associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.[32]

Lymphoblastic lymphoma

Lymphoblastic lymphoma comprises approximately 20% of childhood NHL.[2,3,17] Lymphoblastic lymphomas are usually positive for TdT, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[3,33] Chromosomal abnormalities are not well characterized in patients with lymphoblastic lymphoma.

As many as 75% of patients with lymphoblastic lymphoma will present with an anterior mediastinal mass, which may manifest as dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck. Pleural effusions may be present, and the involvement of lymph nodes, usually above the diaphragm, may be a prominent feature. There may also be involvement of bone, skin, bone marrow, CNS, abdominal organs (but rarely bowel), and occasionally other sites such as lymphoid tissue of Waldeyer ring and testes. Abdominal involvement is less than observed in Burkitt lymphoma. Low-stage lymphoblastic lymphoma may occur in lymph nodes, bone, testes, or subcutaneous tissue. Lymphoblastic lymphoma within the mediastinum is not considered low-stage disease.

Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma with bone marrow involvement or leukemia with extramedullary disease. Traditionally, patients with more than 25% marrow blasts are considered to have leukemia, and those with fewer than 25% marrow blasts are considered to have lymphoma. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.

Anaplastic large cell lymphoma

Anaplastic large cell lymphoma accounts for approximately 10% of childhood NHL.[17] While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or NK-cell surface antigen expression) does occur. The WHO classification system classifies anaplastic large cell lymphoma as a peripheral T-cell lymphoma.[4] Many view ALK-positive anaplastic large cell lymphoma differently than other peripheral T-cell lymphoma because prognosis tends to be superior to other forms of peripheral T-cell lymphoma.[34] All anaplastic large cell lymphoma cases are CD30-positive and more than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM-ALK; the other 15% of cases are comprised of variant ALK translocations.[35] Anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining only of ALK is associated with the variant ALK translocations.[35] There is no correlation between outcome and ALK translocation type.[36] In a series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002).[37]

Clinically, systemic anaplastic large cell lymphoma has a broad range of presentations, including involvement of lymph nodes and a variety of extranodal sites, particularly skin and bone and, less often, gastrointestinal tract, lung, pleura, and muscle. Involvement of the CNS and bone marrow is uncommon. Anaplastic large cell lymphoma is often associated with systemic symptoms (e.g., fever, weight loss) and a prolonged waxing and waning course, making diagnosis difficult and often delayed. Patients with anaplastic large cell lymphoma may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis.[38] There is a subgroup of anaplastic large cell lymphoma with leukemic peripheral blood involvement. These patients usually exhibit significant respiratory distress with diffuse lung infiltrates or pleural effusions and have hepatosplenomegaly. Most of these patients have an aberrant T-cell immunophenotype with frequent expression of myeloid antigens. Patients in this anaplastic large cell lymphoma subgroup may require more aggressive therapy.[39,40]

Lymphoproliferative disease associated with immunodeficiency in children

The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The cause of such immune deficiencies may be a genetically inherited defect, secondary to human immunodeficiency virus (HIV) infection, or iatrogenic following transplantation (solid organ transplantation or allogeneic hematopoietic stem cell transplantation [HSCT]). Epstein-Barr virus (EBV) is associated with most of these tumors, but some tumors are not associated with any infectious agent.

NHL associated with HIV is usually aggressive, with most cases occurring in extralymphatic sites.[41] HIV-associated NHL can be broadly grouped into three subcategories: (1) systemic (nodal and extranodal), (2) primary CNS lymphoma, and (3) body cavity–based lymphoma, also referred to as primary effusion lymphoma. Approximately 80% of all NHL in HIV patients is considered to be systemic.[41] Primary effusion lymphoma, a unique lymphomatous effusion associated with the human herpesvirus-8 (HHV8) gene or Kaposi sarcoma herpesvirus, is primarily observed in adults infected with HIV but has been reported in HIV-infected children.[42] Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for primary CNS lymphoma cases.[43,44] Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum, including primary effusion lymphoma, primary CNS lymphoma, mucosa-associated lymphoid tissue (MALT),[45] Burkitt lymphoma,[46] and diffuse large B-cell lymphoma. NHL in children with HIV often presents with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms.[41]

NHL observed in primary immunodeficiency usually shows a mature B-cell phenotype and large cell histology.[5] Mature T-cell lymphoma and anaplastic large cell lymphoma have been observed.[5] Children with primary immunodeficiency and NHL are more likely to have high-stage disease and present with symptoms related to extranodal disease, particularly the gastrointestinal tract and CNS.[5]

PTLD represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLD following HSCT is associated with EBV, but EBV-negative PTLD can be seen following solid organ transplant.[47] The WHO has classified PTLD into the following three subtypes:[6]

Monomorphic PTLD – Histologies observed in the monomorphic subtype are similar to those observed in NHL, with diffuse large B-cell lymphoma being the most common histology, followed by Burkitt lymphoma, with myeloma or plasmacytoma occurring rarely.

The B-cell stimulation by EBV may result in multiple clones of proliferating B cells, and both polymorphous and monomorphous histologies may be present in a patient, even within the same lesion of PTLD.[48] Thus, histology of a single biopsied site may not be representative of the entire disease process. Not all PTLD is B-cell phenotype.[6] EBV lymphoproliferative disease posttransplant may manifest as isolated hepatitis, lymphoid interstitial pneumonitis, meningoencephalitis, or an infectious mononucleosis-like syndrome. The definition of PTLD is frequently limited to lymphomatous lesions (low stage or high stage), which are often extranodal (frequently in the allograft).[47] Although less common, PTLD may present as a rapidly progressive, high-stage disease that clinically resembles septic shock, which almost always results in death despite therapy.[49]

Rare NHL occurring in children

Low- or intermediate-grade mature B-cell lymphomas, such as small lymphocytic lymphoma, MALT lymphoma, mantle cell lymphoma, myeloma, or follicular cell lymphoma, are rarely seen in children. The most recent WHO classification has identified pediatric follicular lymphoma and pediatric nodal marginal zone lymphoma as unique entities.[1]

Pediatric follicular lymphoma is a disease that differs from the adult counterpart genetically and clinically. The genetic hallmark of adult follicular lymphoma, the translocation of t(14;18)(q32;q21) involving BCL2, is typically not detectable in pediatric follicular lymphoma.[50-52] Molecular alterations observed in pediatric follicular lymphoma include translocations of the immunoglobulin locus and IRF4, losses of regions of chromosome 1p, and mutations of TNFSFR14 on chromosome 1p.[32,53]

Pediatric follicular lymphoma predominantly occurs in males, is associated with a high proliferation rate, is more likely to be localized disease, and has an EFS of approximately 94%.[54] In contrast, adult follicular lymphoma usually presents as disseminated disease with a relatively low proliferation rate.[50,51,55] Cervical lymph nodes and tonsils are common sites, but disease has also occurred in extranodal sites such as the testis, kidney, gastrointestinal tract, and parotid.[50-52,55-57] The outcome of pediatric follicular lymphoma is excellent, and in contrast to adult follicular lymphoma, the clinical course is not dominated by relapses.[50,52,55,56] One study suggested that for children with stage I disease who had a complete resection, a “watch and wait” approach without chemotherapy may be indicated.[54] Patients with higher-stage disease also had a favorable outcome with low- and intermediate-intensity chemotherapy with 94% EFS and 100% OS, with a 2-year median follow-up. It appears that BCL2-rearrangement negativity and high proliferative index predict favorable disease.[50] In pediatric follicular lymphoma, a high-grade component (i.e., grade 3) resembling diffuse large B-cell lymphoma can frequently be detected at initial diagnosis but does not indicate a more aggressive clinical course in children.[50,52,55]

Other diseases appear to reflect the disease observed in adult patients. For example, MALT lymphomas observed in pediatric patients usually present as low-stage (stage I or II) disease, and pediatric gastric MALT lymphomas are associated with Helicobacter pylori and require no more than local therapy involving curative surgery and/or radiation therapy.[58] Conjunctival MALT lymphomas are often associated with chlamydial psittaci infections.[59] Intralesional interferon-alpha for conjunctival MALT lymphoma has been described.[60]

Other types of NHL may be rare in adults and are exceedingly rare in pediatric patients, such as primary CNS lymphoma. Due to small numbers, it is difficult to ascertain if the disease observed in children is the same as in adults and, therefore, it is difficult to determine optimal therapy. Reports suggest that the outcome of pediatric patients with primary CNS lymphoma (OS, 70%–80%) may be superior to that of adults with primary CNS lymphoma. These reports suggest that long-term survival can be achieved without cranial irradiation.[61-65] Most children have diffuse large B-cell lymphoma or anaplastic large cell lymphoma. Therapy with high-dose intravenous methotrexate and cytosine arabinoside is most successful and intrathecal chemotherapy may be needed only when malignant cells are present in the cerebral spinal fluid.[62,64] There is a case report of repeated doses of rituximab, both intravenous and intraventricular, being administered to a 14-year-old boy with refractory primary CNS lymphoma, with an excellent result.[66] This apparently good outcome needs to be confirmed, especially since similar results have not been observed in adults. (Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information on treatment options for nonacquired immunodeficiency syndrome–related primary CNS lymphoma.)

Peripheral T-cell lymphoma, excluding anaplastic large cell lymphoma, is rare in children. Mature T-cell/NK-cell lymphoma or peripheral T-cell lymphoma has a postthymic phenotype (e.g., TdT negative), usually expresses CD4 or CD8, and has rearrangement of T-cell receptor (TCR) genes, either alpha/beta and/or gamma/delta chains. The most common phenotype observed in children is peripheral T-cell lymphoma-not otherwise specified, although angioimmunoblastic lymphoma, enteropathy-associated lymphoma (associated with celiac disease), subcutaneous panniculitis-like lymphoma, angiocentric lymphoma, and extranodal NK/T-cell peripheral T-cell lymphoma have been reported.[67-69] Mycosis fungoides has rarely been reported in children and adolescents.[70] A Japanese study described extranodal NK/T-cell lymphoma, nasal type as the most common peripheral T-cell lymphoma subtype among Japanese children (10 of 21 peripheral T-cell lymphoma cases). In adults, extranodal NK/T-cell lymphoma, nasal type is generally EBV-positive, and 60% of the cases observed in Japanese children were EBV-positive.[71] Though very rare, hepatosplenic T-cell lymphoma is associated with children and adolescents who have Crohn disease and have been on immunosuppressive therapy; this lymphoma has been fatal in all cases.[72]

Optimal therapy for peripheral T-cell lymphoma is unclear, even for adult patients. There have been three retrospective analyses of treatment and outcome for pediatric patients with peripheral T-cell lymphoma. The United Kingdom Children's Cancer Study Group (UKCCSG) reported on 25 children diagnosed over a 20-year period with peripheral T-cell lymphoma, with an approximate 50% 5-year survival rate.[67] The UKCCSG also observed that the use of acute lymphoblastic leukemia (ALL)–like therapy, instead of NHL therapy, produced a superior outcome. The Children's Oncology Group (COG) reported 20 patients older than 8 years treated on Pediatric Oncology Group NHL trials.[68] Eight of ten patients with low-stage disease achieved long-term disease-free survival compared to only four of ten patients with high-stage disease. A study of Japanese children with peripheral T-cell lymphoma (N = 21) reported a 5-year OS rate of 85.2%. Treatment for peripheral T-cell lymphoma was not consistent in this study and included chemotherapy (n = 18), radiation (n = 2), and autologous (n = 2) and allogeneic (n = 9) stem cell transplantation.[71]

An oral retinoid (bexarotene) has been reported to be active against subcutaneous panniculitis-like T-cell lymphomas and cutaneous gamma-delta T-cell lymphomas in a series of 15 patients from three institutions.[73]

In an attempt to learn more about the clinical and pathologic features of these types of NHL seen rarely in children, the COG has opened a registry study (COG-ANHL04B1). This study banks tissue for pathobiology studies and collects limited data on clinical presentation and outcome of therapy.

Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005. [PUBMED Abstract]

Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007. [PUBMED Abstract]

Stage Information for Childhood NHL

The most widely used
staging scheme for childhood non-Hodgkin lymphoma (NHL) is that of the St. Jude Children’s Research Hospital (Murphy Staging).[1]

Stage I Childhood NHL

In stage I childhood NHL, a single tumor or nodal area is involved, excluding the
abdomen and mediastinum.

Stage II Childhood NHL

In stage II childhood NHL, disease extent is limited to a single tumor with
regional node involvement, two or more tumors or nodal areas involved on one side of the
diaphragm, or a primary gastrointestinal tract tumor (completely resected) with or without
regional node involvement.

Stage III Childhood NHL

In stage III childhood NHL, tumors or involved lymph node areas occur on both
sides of the diaphragm. Stage III NHL also includes any primary intrathoracic (mediastinal, pleural, or thymic) disease, extensive primary intra-abdominal
disease, or any paraspinal or epidural tumors.

Stage IV Childhood NHL

Bone marrow involvement has been defined as 5% malignant cells in an otherwise normal bone marrow with normal peripheral blood counts and smears. Patients with lymphoblastic lymphoma with more than 25% malignant cells in the bone marrow are usually considered to have leukemia and may be appropriately treated on leukemia clinical trials.

CNS disease in lymphoblastic lymphoma is defined by criteria similar to that used for acute lymphocytic leukemia (i.e., white blood cell count of at least 5/μL and malignant cells in the cerebrospinal fluid [CSF]). For any other NHL, the definition of CNS disease is any malignant cell present in the CSF regardless of cell count. The Berlin-Frankfurt-Munster (BFM) group analyzed the prevalence of CNS involvement in NHL in over 2,500 patients.[2] Overall, CNS involvement was diagnosed in 6% of patients. Involvement by cell type was as follows:

Burkitt lymphoma/leukemia: 8.8%

Precursor B-cell lymphoblastic lymphoma: 5.4%

T-cell lymphoblastic lymphoma: 3.7%

Anaplastic large cell lymphoma: 3.3%

Diffuse large B-cell lymphoma: 2.6%

Primary mediastinal large B-cell lymphoma: 0%

Mature B-cell NHL (Burkitt lymphoma and diffuse large B-cell lymphoma) patients have been treated based on features of the disease, other than stage.

Treatment Option Overview

Many of the improvements in childhood cancer survival have been made using
combinations of known and/or new agents that have attempted to improve the
best available, accepted therapy. Clinical trials in pediatrics are designed
to compare potentially better therapy with therapy that is currently accepted
as standard. This comparison may be done in a randomized study of two treatment
arms or by evaluating a single new treatment and comparing the results with
those previously obtained with standard therapy.

All children with non-Hodgkin lymphoma (NHL) should be considered for entry
into a clinical trial. Treatment planning by a multidisciplinary team of
cancer specialists with experience treating tumors of childhood is strongly
recommended to determine, coordinate, and implement treatment to achieve
optimal survival. Children with NHL should be referred for treatment by a
multidisciplinary team of pediatric oncologists at an institution with
experience in treating pediatric cancers. Information about ongoing clinical
trials is available from the NCI Web site.

NHL in children is generally considered to be widely disseminated from the
outset, even when apparently localized; as a result, combination chemotherapy
is recommended for most patients.[1]

In contrast to the treatment of adults with NHL, the use of radiation therapy is limited in children with NHL. Early studies demonstrated that the routine use of radiation had no benefit for low-stage (I or II) NHL.[2] It has been demonstrated that prophylactic central nervous system (CNS) radiation can be omitted in lymphoblastic lymphoma.[3,4] It has also been demonstrated that CNS radiation can be eliminated for patients with anaplastic large cell lymphoma and B-cell NHL, even for patients who present with CNS disease.[5,6] Further data to support the limited use of radiation in pediatric NHL comes from the Childhood Cancer Survivor Study.[7] This analysis demonstrated that radiation was a significant risk factor for secondary malignancy and death in long-term survivors.

Treatment of NHL in childhood and adolescence has historically been based on clinical behavior and response to treatment. A study by the Children’s Cancer Group demonstrated that the outcome for lymphoblastic NHL was superior with longer acute lymphoblastic leukemia–like therapy, while nonlymphoblastic NHL (Burkitt lymphoma) had superior outcome with short, intensive, pulsed therapy.[8]

Medical Emergencies

There are two potentially life-threatening
clinical situations that are often seen in children with NHL: (1) mediastinal masses and (2) tumor lysis syndrome, most often seen in lymphoblastic and Burkitt or Burkitt-like NHL. These emergent situations should be anticipated in
children with NHL and addressed immediately.

Mediastinal masses

Patients with large mediastinal masses are at risk of cardiac or respiratory
arrest during general anesthesia or heavy sedation.[9] Due to the risks of
general anesthesia or heavy sedation, a careful physiologic and radiographic
evaluation of the patient should be carried out and the least invasive
procedure should be used to establish the diagnosis of lymphoma.[10,11] Bone
marrow aspirate and biopsy should always be performed early in the workup of
these patients. If a pleural effusion is present, a cytologic diagnosis is
frequently possible using thoracentesis. In those children who present with
peripheral adenopathy, a lymph node biopsy under local anesthesia and in an
upright position may be possible.[12] In situations in which the above
diagnostic procedures are not fruitful, consideration of a computed tomography (CT)–guided core
needle biopsy should be contemplated. This procedure can frequently be carried
out using light sedation and local anesthesia before proceeding to more
invasive procedures. Care should be taken to keep patients out of a supine position. Most procedures, including CT scans, can be done with the patient on their side or prone. Mediastinoscopy, anterior mediastinotomy, or thoracoscopy
are the procedures of choice when other diagnostic modalities fail to establish
the diagnosis. A formal thoracotomy is rarely, if ever, indicated for the
diagnosis or treatment of childhood lymphoma. Occasionally, it will not be
possible to perform a diagnostic operative procedure because of the risk of
general anesthesia or heavy sedation. In these situations, preoperative
treatment with steroids or localized radiation therapy should be considered.
Since preoperative treatment may affect the ability to obtain an accurate
tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risk of
general anesthesia or heavy sedation is thought to be alleviated.

Tumor lysis syndrome

Tumor lysis syndrome results from rapid breakdown of malignant cells, resulting
in a number of metabolic abnormalities, most notably hyperuricemia,
hyperkalemia, and hyperphosphatemia. Hyperhydration and allopurinol or
rasburicase (urate oxidase) are essential components of therapy in all patients except those with the most limited disease.[13-17] An initial prephase consisting of low-dose
cyclophosphamide and vincristine does not obviate the need for
allopurinol or rasburicase and hydration. Gastrointestinal bleeding, obstruction, and
(rarely) perforation may occur. Hyperuricemia and tumor lysis syndrome,
particularly when associated with ureteral obstruction, frequently result in
life-threatening complications. Patients with NHL should be managed only in
institutions having pediatric tertiary care facilities.

Role of Radiographic Imaging in Childhood NHL

Radiographic imaging is essential in the staging of patients with NHL. Ultrasound may be the preferred method for assessment of an abdominal mass, but CT scan and, more recently, magnetic resonance imaging (MRI) have been used for staging. Radionucleotide bone scans should be considered for patients where bone involvement is suspected.

The role of functional imaging in pediatric NHL is controversial. Gallium scans have been replaced by fluorodeoxyglucose positron emission tomography (PET) scanning, which is now routinely performed at many centers.[18] A review of the revised International Workshop Criteria comparing CT imaging alone or CT together with PET imaging demonstrated that the combination of CT and PET imaging was more accurate than CT imaging alone.[19,20] While the International Harmonization Project for PET (now called the International Working Group) response criteria have been attempted in adults, they have yet to be evaluated in pediatric populations.[18,21] This International Working Group has updated their response criteria for malignant lymphoma to include PET, immunohistochemistry, and flow cytometry data.[20]

The value of PET scanning for staging pediatric NHL is under investigation.[22] Data support that PET identifies more abnormalities than CT scanning, but it is unclear whether this should be used to change therapy.[23]

The use of PET to assess rapidity of response to therapy appears to have prognostic value in Hodgkin lymphoma and some types of NHL observed in adult patients, and this is also under investigation in pediatric NHL. However, there are no data in pediatric NHL to support the hypothesis that early response to therapy assessed by PET has prognostic value.

Caution should be used in making the diagnosis of relapsed disease based solely on imaging because false-positive results are common.[24-28] There are also data demonstrating that PET scanning can produce false-negative results.[29] Before undertaking changes in therapy based on residual masses noted by imaging, a biopsy to prove residual disease is warranted.

Low-Stage Childhood NHL Treatment

Patients with stage I and II disease have an excellent prognosis, regardless of histology. A Children’s Cancer Group study demonstrated that pulsed chemotherapy with cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) administered for 6 months for low-stage (stage I or II) nonlymphoblastic non-Hodgkin lymphoma (NHL) was equivalent to 18 months of therapy with radiation to sites of disease, resulting in more than 85% disease-free survival (DFS) and more than 90% overall survival (OS). However, patients with lymphoblastic lymphoma had a much inferior outcome.[1,2] A Pediatric Oncology Group (POG) study tested 9 weeks of short, pulsed chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), with or without radiation to involved sites and with or without 24 weeks of maintenance chemotherapy.[3] The results showed no benefit of radiation or maintenance chemotherapy, but the DFS for nonlymphoblastic lymphoma was superior to that of lymphoblastic lymphoma (90% vs. 60%).

For low-stage mature B-cell NHL (Burkitt lymphoma or diffuse large B-cell lymphoma), DFS is about 95%. The Berlin-Frankfurt-Munster (BFM) group has treated risk group R1 (completely resected disease) with two cycles of multiagent chemotherapy (GER-GPOH-NHL-BFM-90 and GER-GPOH-NHL-BFM-95).[4,5] For unresected stage I/II disease (R2), patients received a cytoreductive phase followed by five cycles of chemotherapy.[4,5] In the NHL-BFM-90 study, it was shown that reducing the dose of methotrexate did not affect the results for low-stage disease.[4] In NHL-BFM-95, it was demonstrated for low-stage disease that prolonging the duration of methotrexate infusion did not improve outcome.[5] The French Society of Pediatric Oncology (SFOP) and French-American-British (FAB) studies have treated all completely resected stage I and abdominal stage II (group A) with two cycles of multiagent chemotherapy, without intrathecal chemotherapy (COG-C5961 [FAB/LMB-96]).[6][Level of evidence: 2A] For unresected stage I/II disease (group B), the above-mentioned FAB study demonstrated that reducing the duration of therapy to four cycles of chemotherapy following a cytoreduction phase and reducing the cumulative doses of cyclophosphamide and doxorubicin did not affect outcome.[7]

For low-stage lymphoblastic lymphoma (stage I/II disease), about 60% of patients can achieve long-term DFS with short, pulsed chemotherapy.[2,3] However, with the use of an acute lymphoblastic leukemia approach with induction, consolidation, and maintenance therapy for a total of 24 months, DFS rates higher than 90% have been reported for children with low-stage lymphoblastic lymphoma.[8-10]

For low-stage anaplastic large cell lymphoma, the best results have come from using pulsed chemotherapy similar to mature B-cell NHL therapy. In the POG study for low-stage lymphoma using three cycles of CHOP, a 5-year event-free survival (EFS) of 88% for large cell lymphoma (anaplastic large cell lymphoma and diffuse large B-cell lymphoma) patients was reported.[3] The BFM group has used three cycles of chemotherapy following a cytoreductive prophase for completely resected stage I/II disease.[11] The FRE-IGR-ALCL99 trial used three cycles of chemotherapy following cytoreductive prophase for patients with stage I completely resected disease. The minority of stage I patients had complete resections (6 out of 36) but there were no treatment failures for these six patients. The therapy for patients without complete resection was the same as the therapy for patients with disseminated disease and the 3-year EFS (81%) and OS (97%) were not statistically different from the outcomes for patients with higher stage disease.[12][Level of evidence: 2A]

Primary cutaneous anaplastic large cell lymphoma presents a particular problem. The diagnosis can be difficult to distinguish from more benign diseases such as lymphoid papulosis.[13] Primary cutaneous anaplastic large cell lymphoma usually does not express ALK and may be treated successfully with surgical resection and/or local radiation therapy without systemic chemotherapy.[14] There are reports of surgery alone being curative for ALK-positive cutaneous anaplastic large cell lymphoma, but extensive staging and vigilant follow-up is required.

Follicular lymphoma is rare in children, with only case reports and case series to guide therapy. Although outcome is generally very good, treatments range from surgery only to multiagent chemotherapy and even autologous blood or marrow transplant.[15-20] It appears that for pediatric patients without the BCL2 rearrangement and a high proliferative index, surgical resection with no further treatment is sufficient for completely resected, localized disease. For those with tumors that have the BCL2 rearrangement, treatment like that of adult patients with follicular lymphoma is preferred (refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information).

Subcutaneous mature T-cell lymphomas are very rare in children. An oral retinoid (bexarotene) has been reported to be active against subcutaneous T-cell lymphomas in children.[21]

Standard treatment options are based on histology; however, current data do not suggest superiority between regimens listed below for a specific histology.

Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005. [PUBMED Abstract]

High-Stage Childhood B-cell NHL Treatment

Patients with high-stage (stage III or stage IV) mature B-lineage non-Hodgkin lymphoma (NHL) (Burkitt or Burkitt-like lymphoma and diffuse large B-cell lymphoma) have an 80% to 90% long-term survival.[1-3] Unlike mature B-lineage NHL seen in adults, there is no difference in outcome based on histology (Burkitt or Burkitt-like lymphoma or diffuse large B-cell lymphoma) with current therapy in pediatric trials.[1-3]

Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma or leukemia. Traditionally, patients with more than 25% marrow blasts are classified as having mature B-cell leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not clear whether these arbitrary definitions are biologically distinct, but there is no question that patients with Burkitt leukemia should be treated with protocols designed for Burkitt lymphoma.[1,3]

Tumor lysis syndrome is often present at diagnosis or after initiation of treatment. This emergent clinical situation should be anticipated and addressed before treatment is started. (Refer to the Tumor lysis syndrome subsection in the Treatment Option Overview section of this summary for more information.) For reduction of the complications of tumor lysis syndrome, current treatment regimens use a prophase of reduced intensity to cytoreduce patients;[1-3] however, this does not obviate the use of hyperhydration and allopurinol or rasburicase (urate oxidase). Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently
result in life-threatening complications. Gastrointestinal bleeding, obstruction, and (rarely) perforation may occur. Patients with NHL should be managed only in institutions having pediatric tertiary care facilities.[4]

In the NHL-BFM-95 trial, it was shown that when the dose of methotrexate was reduced for R1 and R2 patients, outcome was not inferior; however, reducing the infusion time of methotrexate from 24 hours to 4 hours for R3 and R4 group patients resulted in less mucositis, but inferior outcome.[1] Event-free survival (EFS) with best therapy in NHL-BFM-95 was more than 95% for R1 and R2 group patients and was 93% for R3 and R4 group patients. Inferior outcome was observed for patients with primary mediastinal B-cell lymphoma (50% 3-year EFS) and CNS disease at presentation (70% 3-year EFS).[5] In the COG-C5961 (FAB/LMB-96) study, the outcome of group B patients, who had a greater than 20% response to cytoreductive prophase, was not affected by a reduction of the total dose of cyclophosphamide by 50% and elimination of one cycle of maintenance therapy.[2] The 3-year EFS was 98% for stage I/II, 90% for stage III, and 86% for stage IV (CNS-negative) patients, while patients with primary mediastinal B-cell lymphoma had a 3-year EFS of 70%.[2] In group C patients, reduction in cumulative dose of therapy and number of maintenance cycles resulted in inferior outcome.[3] Patients with leukemic disease only, and no CNS disease, had a 3-year EFS of 90%, while patients with CNS disease at presentation had a 70% 3-year EFS.[3] This study identified response to prophase reduction as the most significant prognostic factor, with poor responders (i.e., <20% resolution of disease) having an EFS of 30%.[3] Both the Berlin-Frankfurt-Munster (BFM) and FAB/LMB studies demonstrated that omission of craniospinal irradiation, even in patients presenting with CNS disease, does not affect outcome (COG-C5961 [FAB/LMB-96] and NHL-BFM-90 [GER-GPOH-NHL-BFM-90]).[1-3,5]

Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Among the lymphomas that occur in children, diffuse large B-cell lymphoma and Burkitt lymphoma both express high levels of CD20.[6] Rituximab has been safely combined with standard doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) chemotherapy and has been shown to improve outcome in a randomized trial of adults with diffuse large B-cell lymphoma (CAN-NCIC-LY9).[7,8] In an adult study, rituximab has also been safely combined with an intensive chemotherapy regimen used to treat patients with Burkitt lymphoma.[9] In children, a single-agent phase II study of rituximab performed by the BFM group showed activity in Burkitt leukemia and lymphoma.[10][Level of evidence: 2Div] A Children's Oncology Group (COG) pilot study (COG-ANHL01P1) added rituximab to baseline chemotherapy with FAB/LMB-96 therapy in patients with stage III and stage IV B-cell NHL; compared with chemotherapy-only protocols, toxicity was similar, despite a trend toward higher peak rituximab levels in younger patients.[11]; [12][Level of evidence: 3iiiA] The addition of rituximab to standard chemotherapy is now being tested in a randomized trial.

Standard Treatment Options

[Note: Current data do not suggest superiority for either of the following standard treatment options.]

Treatment Options Under Clinical Evaluation

The following is an example of a national or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

COG-ANHL1131 (Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III–IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia): This randomized study of patients with high-risk disease (defined as Group B with high lactate dehydrogenase and Group C) examines the addition of rituximab to the standard FAB LMB 96 (COG-C5961) chemotherapy regimen. Additionally, the dose-adjusted EPOCH-R regimen (etoposide, prednisone, vincristine, doxorubicin, and rituximab) will be tested in a single-arm, phase II trial for pediatric patients with primary mediastinal B-cell lymphoma.

General information about clinical trials is also available from the NCI Web site.

References

Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005. [PUBMED Abstract]

Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007. [PUBMED Abstract]

High-Stage Childhood Lymphoblastic Lymphoma Treatment

Patients with high-stage (stage III or IV) lymphoblastic lymphoma have long-term survival rates higher than 80%.[1] Unlike other pediatric non-Hodgkin lymphoma (NHL), it has been shown that lymphoblastic lymphoma responds much better to leukemia therapy with 2 years of therapy than with shorter, intensive, pulsed chemotherapy regimens.[1-3]

Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma or leukemia. Traditionally, patients with more than 25% marrow blasts are classified as having leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design. All current therapies for advanced-stage lymphoblastic lymphoma have been derived from regimens designed for the treatment of acute lymphoblastic leukemia (ALL).

Mediastinal radiation is not necessary for patients with mediastinal masses, except in the emergency treatment of symptomatic superior vena caval obstruction or airway obstruction, where either corticosteroid therapy or low-dose radiation is usually employed. (Refer to the Treatment Option Overview section of this summary for more information on such complications.) Because of the complexities of optimal therapeutic regimens and the possibility of toxic side effects, patients should be offered the opportunity to enter into a clinical trial. Information about ongoing clinical trials is available from the NCI Web site.

The best results to date come from the Berlin-Frankfurt-Munster (BFM) group. In the GER-GPOH-NHL-BFM-90 study, the 5-year disease-free survival was 90%, and there was no difference in outcome between stage III and stage IV patients.[1] Precursor B-cell lymphoblastic lymphoma appears to have similar results using the same therapy.[4] In the GER-GPOH-NHL-BFM-95 study, the prophylactic cranial radiation was omitted, and the intensity of induction therapy was decreased slightly. There were no significant increases in central nervous system (CNS) relapses, suggesting cranial radiation may be reserved for patients with CNS disease at diagnosis.[3] Of interest, the probability of 5-year
event-free survival (EFS) rates was worse in NHL-BFM-95 than in NHL-BFM-90 (82%
vs. 90%, respectively). Although this difference was not statistically different, NHL-BFM-95 had a reduction of asparaginase and doxorubicin in induction, which may have affected outcome. It was proposed that the major difference in EFS between NHL-BFM-90 and NHL-BFM-95 resulted from the increased number of secondary malignancies observed in NHL-BFM-95.[3] A single-center study suggests that patients treated for lymphoblastic lymphoma have a higher incidence of secondary malignancy than do patients treated for other pediatric NHL; however, studies from the Children's Oncology Group and the Childhood Cancer Survivor Study Group do not support this finding.[5-8]

The Pediatric Oncology Group conducted a trial to test the effectiveness of the addition of high-dose methotrexate in T-cell ALL and T-cell lymphoblastic lymphoma. In the lymphoma patients, high-dose methotrexate did not demonstrate benefit. However, in the small cohort (n = 66) of lymphoma patients who did not receive high-dose methotrexate, the 5-year EFS was 88%.[9][Level of evidence: 1iiA] Of note, all of these patients received prophylactic craniospinal radiation therapy, which has been demonstrated not to be required in T-cell lymphoblastic lymphoma patients.[3]

Standard Treatment Options

[Note: Current data do not suggest superiority for the following standard treatment options.]

High-Stage Childhood Anaplastic Large Cell Lymphoma Treatment

Children and adolescents with high-stage (stage III or IV) anaplastic large cell lymphoma have a disease-free survival of approximately 60% to 75%.[1-6] It is unclear which strategy is best for the treatment of high-stage anaplastic large cell lymphoma. The German Berlin-Frankfurt-Munster (BFM) group used six cycles of intensive pulsed therapy, similar to their B-cell non-Hodgkin lymphoma (NHL) therapy (GER-GPOH-NHL-BFM-90 [NHL-BFM-90]).[2]; [7][Level of evidence: 1iiA] Building on these results, the European Intergroup for Childhood NHL (EICNHL) group conducted the FRE-IGR-ALCL99 study (based on the GER-GPOH-NHL-BFM-90 regimen). First, this randomized study demonstrated that methotrexate 1 g/m2 infused over 24 hours plus intrathecal methotrexate and methotrexate 3 g/m2 infused over 3 hours without intrathecal methotrexate yielded similar outcomes.[8][Level of evidence: 1iiC] However, methotrexate 3 g/m2 over 3 hours had less toxicity than methotrexate 1 g/m2 over 24 hours.[8]; [7][Level of evidence: 1iiDi] Secondly, FRE-IGR-ALCL99 randomly assigned patients to limited vinblastine versus prolonged (1 year) vinblastine exposure. Patients receiving the vinblastine plus chemotherapy regimen had a better event-free survival (EFS) in the first year after therapy (91%) than those not receiving vinblastine (74%); however, after 2 years of follow-up, the EFS was 73% for both groups.[9][Level of evidence: 1iiDi] Of note, the Pediatric Oncology Group (POG) trial (POG-9317) demonstrated no benefit of adding methotrexate and high-dose cytarabine to 52 weeks of the APO (doxorubicin, prednisone, and vincristine) regimen.[3] The Italian Association of Pediatric Hematology/Oncology group has used a leukemia-like regimen for 24 months in LNH-92, with similar results as other regimens.[4] The CCG-5941 study tested an approach similar to LNH-92, with more intensive induction and consolidation with maintenance for 1 year total duration of therapy, with similar outcome, but significant hematologic toxicity was observed.[5][Level of evidence: 2A]

Central nervous system (CNS) involvement in anaplastic large cell lymphoma is rare at diagnosis. In an international study of systemic childhood anaplastic large cell lymphoma, 12 of 463 (2.6%) patients had CNS involvement, three of whom had isolated CNS disease. With multiagent chemotherapy, including high-dose methotrexate, cytarabine,
and intrathecal treatment, the event-free survival and overall survival of the CNS-positive group at 5 years were 50% (95% CI, 25%–75%) and 74% (45%–91%), respectively, with a median follow up of 4.1 years. The role of cranial radiation therapy is difficult to assess.[10]

Standard Treatment Options

[Note: Current data do not suggest superiority for the following standard treatment options.]

APO: doxorubicin, prednisone, and vincristine.[3] This regimen can be administered in the outpatient setting. The duration of therapy is 52 weeks and the cumulative dose of doxorubicin in 300 mg/m2.

FRE-IGR-ALCL99: dexamethasone, cyclophosphamide, ifosfamide, etoposide, doxorubicin, IV methotrexate (3 g/m2 arm), cytarabine, prednisolone, and vinblastine.[7] This regimen usually requires hospitalization for administration. The total duration of therapy is 5 months and the cumulative dose of doxorubicin is 150 mg/m2.

Recurrent Childhood NHL Treatment

Outcome for recurrent non-Hodgkin lymphoma (NHL) in children and adolescents depends on histologic subtype. A Children's Cancer Group study (CCG-5912) was able to achieve complete remission (CR) in 40% of NHL patients.[1] A Pediatric Oncology Group study showed a 70% response rate and 40% CR rate.[2] Radiation therapy may have a role in treating patients who have not had a complete response to chemotherapy. All patients with primary refractory or relapsed NHL should be considered for clinical trials.

For recurrent or refractory B-lineage NHL, survival is generally 10% to 20%.[3-7] Chemoresistance is a major problem, making remission difficult to achieve. There is no standard treatment option for patients with recurrent or progressive disease. The use of single-agent rituximab, and rituximab combined with standard cytotoxic chemotherapy, has shown activity in the treatment of B-cell lymphoma patients.[8][Level of evidence: 3iiiDii] A Children's Oncology Group (COG) study using rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) to treat relapsed/refractory B-cell NHL (diffuse large B-cell lymphoma and Burkitt lymphoma) showed a CR/partial remission (PR) rate of 60%.[9][Level of evidence: 3iiA] If remission can be achieved, high-dose therapy and stem cell transplantation (SCT) may be pursued. The benefit of autologous versus allogeneic SCT is unclear.[5,10-12]; [13][Level of evidence: 2A]; [14][Level of evidence: 3iiiDii] (Refer to the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation). An analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) data demonstrated no difference using either autologous or allogeneic donor stem cell sources, with 2-year event-free survival (EFS) to be 30% for diffuse large B-cell lymphoma and 50% for Burkitt lymphoma. This analysis also showed patients not in remission at time of transplant do significantly worse.[12,13] For patients who have a second relapse after initial autologous SCT, an allogeneic SCT was found to be a promising treatment in a study of adults with diffuse large B-cell lymphoma.[15]

For recurrent or refractory lymphoblastic lymphoma, survival in the literature ranges from 10% to 40%.[5,16]; [17,18][Level of evidence: 3iiiA] As with Burkitt lymphoma, chemoresistant disease is common. There is no standard treatment option for patients with recurrent or progressive disease. A COG phase II study of nelarabine (compound 506U78) as a single agent demonstrated a response rate of 40%.[19] The CIBMTR analysis demonstrated that EFS was significantly worse using autologous (4%) versus allogeneic (40%) donor stem cell source, with all failures resulting from progressive disease.[12]

For recurrent or refractory anaplastic large cell lymphoma, 40% to 60% of patients can achieve long-term
survival.[5,20,21] There is no standard approach for recurrent/refractory anaplastic large cell lymphoma; standard chemotherapy, followed by autologous SCT or allogeneic SCT, if remission can be achieved, have all been employed in this setting.[5,12,20,21]; [13][Level of evidence: 2A] In a retrospective study of relapsed or refractory anaplastic large cell lymphoma in patients who received Berlin-Frankfurt-Muenster–type first-line therapy, reinduction chemotherapy followed by autologous stem cell transplant resulted in 59% 5-year EFS and 77% overall survival.[21][Level of evidence: 2A] However, outcome of patients with bone marrow or central nervous system involvement, relapse during first-line therapy, or CD3-positive anaplastic large cell lymphoma was poor. These patients may benefit from allogeneic transplantation.[21] Several additional studies suggest that allogeneic SCT may result in better outcome for refractory/relapsed anaplastic large cell lymphoma.[12,22] Vinblastine
is active as a single agent in recurrent/refractory anaplastic large cell lymphoma, inducing CR in 25 (83%) of 30 evaluable patients in one study.[23] Nine of 25 patients treated with vinblastine alone remained in CR with median follow-up of 7 years since the end of treatment.[23][Level of evidence:
3iiiA]

Crizotinib, a kinase inhibitor that blocks the activity of the NPM-ALK fusion protein, has been evaluated in children and adults with relapsed/refractory anaplastic large cell lymphoma.[24,25] There are two case reports of adults with anaplastic large cell lymphoma who achieved complete responses to crizotinib, and seven of nine children with anaplastic large cell lymphoma treated on the pediatric phase I study of crizotinib achieved complete responses.[24,26]

Brentuximab vedotin has been evaluated in adults with anaplastic large cell lymphoma. A phase I study in adults with CD30-positive cancers identified a recommended phase II dose of 1.8 mg/kg, administered every 3 weeks; two of two patients with anaplastic large cell lymphoma achieved CR.[27] A phase II trial in adults with relapsed anaplastic large cell lymphoma has shown CR rates of approximately 55% to 60% and PR rates of 29%.[28] The number of pediatric patients treated with brentuximab vedotin is not sufficient to determine whether they respond differently than adult patients.

Treatment Options Under Clinical Evaluation

The following is an example of a national or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

COG-ADVL0912 (Crizotinib in Treating Young Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma): The ALK inhibitor, crizotinib, is under phase I evaluation in children. The study has a stratum for children with ALK and anaplastic large cell lymphoma.

COG-ADVL1114 (Temsirolimus, Dexamethasone, Mitoxantrone Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia [ALL] or NHL): This is a phase I trial to determine the feasibility and safety of adding three doses of temsirolimus (intravenously) to the United Kingdom ALLR3 induction regimen for patients with relapsed ALL and NHL.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
recurrent childhood non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Lymphoproliferative Disease Associated With Immunodeficiency in Children

Regardless of the etiology of the immune defect, immunodeficient children with lymphoma have a worse prognosis than does the general population with non-Hodgkin lymphoma (NHL).[1-4] One potential exception is the more indolent low-grade lymphomas (e.g., mucosa-associated lymphoid tissue [MALT] lymphomas), which have developed in patients with common variable immunodeficiency or other immunodeficient states.[5,6] If the disease is localized and amenable to complete surgical resection and/or radiation therapy, the outcome is quite favorable; however, most NHL in this population is high-stage (stage III or IV) and requires systemic cytotoxic therapy. These patients usually tolerate cytotoxic therapy poorly, with increased morbidity and mortality due to increased infectious complications and often increased end-organ toxicities. (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information about MALT lymphomas.)

In the era of highly active antiretroviral therapy, children with human immunodeficiency virus and NHL should be treated with standard chemotherapy regimens for NHL, but careful attention to prophylaxis against and early detection of infection is warranted.[1,7,8] Patients with primary immunodeficiency can achieve complete and durable remissions with standard chemotherapy regimens for NHL, though again, toxicity is increased.[2] Recurrences in these patients are common and may not represent the same clonal disease.[9] Immunologic correction through allogeneic stem cell transplantation is often required to prevent recurrences. Patients with DNA repair defects (e.g., ataxia-telangiectasia) are particularly difficult to treat.[4,10] Cytotoxic agents produce much more toxicity and greatly increase the risk of secondary malignancies in these patients. Survival is rare at 5 years postdiagnosis.

In posttransplant lymphoproliferative disease (PTLD), first-line therapy is the reduction of immunosuppression as can be tolerated.[3,11] Rituximab, an anti-CD20 antibody, has been used with some success, but data for its use in children are sparse. Rituximab plus low-intensity chemotherapy may also be effective, even in posttransplant lymphoproliferative diseases with the t(8;14) Burkitt lymphoma marker.[12][Level of evidence: 3iiDiii] Another larger study suggested that more conventional lymphoma therapy is effective for PTLD with c-myc translocations and Burkitt histology.[13][Level of evidence: 3iiDiii] Patients with T-cell or Hodgkin-like PTLD are usually treated with standard lymphoma-specific chemotherapy regimens.[14-17]

Standard Treatment Options

Treatment Options Under Clinical Evaluation

The following is an example of a national or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

Adoptive immunotherapy with either donor lymphocytes or ex vivo–generated Epstein-Barr virus–specific cytotoxic T-cells have been effective in treating PTLD following blood or bone marrow transplant.[19,20] Though this approach has been demonstrated to be feasible in patients with PTLD following solid organ transplant, it has not been demonstrated to be as effective or practical.

Added text to state that the Berlin-Frankfurt-Munster group reported that in pediatric patients with T-cell lymphoblastic lymphoma, loss of heterozygosity at chromosome 6q was observed in 12% of patients and was associated with unfavorable prognosis. NOTCH1 mutations were seen in 60% of patients and were associated with favorable prognosis; NOTCH1 mutations were rarely seen in patients with loss of heterozygosity in 6q16 (cited Bonn et al. as reference 34).

Added text to state that one study suggested that for children with stage I disease who had a complete resection, a “watch and wait” approach without chemotherapy may be indicated (cited Attarbaschi et al. as reference 54). Also added text to state that patients with higher-stage disease also had a favorable outcome with low- and intermediate-intensity chemotherapy with 94% event-free survival and 100% overall survival, with a 2-year median follow-up; it appears that BCL2-rearrangement negativity and high proliferative index predict favorable disease.

Added text to state that data support that positron emission tomography identifies more abnormalities than computed tomography scanning, but it is unclear whether this should be used to change therapy (cited Cheng et al. as reference 23).

Added text to state that although outcome is generally very good, treatments range from surgery only to multiagent chemotherapy and even autologous blood or marrow transplant. It appears that for pediatric patients without the BCL2 rearrangement and a high proliferative index, surgical resection with no further treatment is sufficient for completely resected, localized disease. For those with tumors that have the BCL2 rearrangement, treatment like that of adult patients with follicular lymphoma is preferred (cited Attarbaschi et. al. as reference 20).

Revised text to state that a Children's Oncology Group pilot study added rituximab to baseline chemotherapy with FAB/LMB-96 therapy in patients with stage III and stage IV B-cell NHL; compared with chemotherapy-only protocols, toxicity was similar, despite a trend toward higher peak rituximab levels in younger patients (cited Barth et al. as reference 11 and Goldman et al. as reference 12 and level of evidence 3iiiA). Also added text to state that the addition of rituximab to standard chemotherapy is now being tested in a randomized trial.

Revised text to state that there are two case reports of adults with anaplastic large cell lymphoma who achieved complete responses to crizotinib, and seven of nine children with anaplastic large cell lymphoma treated on the pediatric phase I study of crizotinib achieved complete responses (cited Mossé et al. as reference 26).

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood non-Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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